Fourth International Electronic Conference on Synthetic Organic Chemistry (ECSOC-4), www.mdpi.org/ecsoc-4.htm, September 1-30, 2000

[A0057]

Diels-Alder cycloadditions of 1,3-cyclohexadien-4,5-diones
(o-benzoquinones) with norbornadiene. Part I. Synthesis.

Martin R. Johnston, Melissa J. Latter, Ronald N. Warrener, Mirta Golic, Dan McKavanagh and Davor Margetic

Centre for Molecular Architecture, Central Queensland University, North Rockhampton, 4701, QLD, Australia
E-mail: [email protected]

Received: 1 August 2000 / Uploaded: 2 August 2000

Abstract. Cycloadditions between o-chloranil and norbornadiene produced a range of geometrical variants which were characterised as quinoxaline derivatives. Two ether products were also observed resulting from hetero Diels-Alder reactions. Photochemical irradiation of 20 produced the cage compound 22 as a result of an internal (2+2)p cycloaddition.

Intoduction. In this paper we describe some syntheses of o-benzoquinone, o-chloranil and 2,5-di-(t-bu)-benzoquinone with norbornadiene.[1,2] The resulting alicyclic a-diones are used in our BLOCK assembly protocols [3] for Schiff�s base condensations with substituted o-phenylene diamines 2 to yield quinoxalines 3 suitable as building BLOCKs (Scheme 1). VRID01SNYAE00 �ySONY HP CD-Writer+ 8200a1.0g��yarious effectors such as porphyrin 7 [4,5], uracil 5 [6] and the 1,10-phenantroline ligand 6 [7] have been attached to these BLOCKs which are then used to prepare large supramolecular systems such as bis-porphyrin host 8 (Scheme 2).

Cycloaddition of o-chloranil. The addition of o-chloranil (10) to norbornadiene (9) (Figure 1) has been previously utilised for the synthesis of the linear a-dione BLOCK (11).[2] However, a closer examination of the crude reaction has revealed the presence of all the possible geometries of addition with the four dione products (11-14) which were characterised as their phenylenediamine condensation products 18-21 (Figure 1) (due to their readiness to add water to form hydrates eg. 11a). The hetero Diels-Alder adducts 15 and 16 are also observed from heteronuclear reaction between 10 and norbornadiene. Standard conditions for this condensation reaction are reflux in ethanol, however we have shown that the same reaction can also be carried out un! der high pressure (in DCM) in high yields. Furthermore, in a separate experiment, a sample of pure hydrate 11a was condensed with phenylene diamine to produce 18 under similar high pressure conditions (DCM, overnight, 53% yield). In contrast, the reaction of parent o-benzoquinone with NBD (Figure 2) yields predominantly the linear exo- adduct 11, with insignificant amounts of the other isomers.

In the case of o-chloranil and norbornadiene, a study was undertaken in order to establish the effects of temperature and solvent on the distribution of these adducts. The reaction of 9 and 10 was studied in benzene, chloroform and ethanol at several temperatures (ambient, 50 and 80 ^oC). The reaction solutions were immediately treated with o-phenylenediamine, ethanol added, and the mixture heated at reflux for 1 hour. After workup, the solutions were examined by HPLC (normal phase) to determine the isomer distribution. The retention times for each of the compounds was determined by partial column chromatographic separation (silica) of the various fractions coupled with ¹H-NMR spectra. The ether by-products were readily identifiable by their lack of proton resonances in the aromatic region and bicyclo[2.2.2] olefinic proton resonances, while the endo- addition pro! ducts were characterised by their characteristic chemical shifts and coupling patterns. For instance, in compound 18, the methylene protons Ha and Hb reso nate at (d=2.00 and 2.42 respectively), whereas in 19 where these protons experience a large shielding by the proximal aromatic ring and resonate at d -0.67 and 0.85, respectively. There was no significant chemical shift of olefinic proton Hc in structure 20 as compared to compounds 18 and 19 (d=6.21, 6.33 and 6.19, respectively). In addition, the formation of the cage compound 22 from irradiation of quinoxaline 20 confirmed the assignment of the endo- addition products.

The results are summarised in Table 1 and reveal that the exo-linear adduct 18 is always the major addition product, followed by the endo-linear product 20. The amount of products such as 20 and 21 increases as solvents other than ethanol are investigated explaining one possible reason why these compounds where not observed in earlier studies. The zero values shown in the table indicate that no amount of that isomer was observable using UV detection (254 nm).

An understanding of the isomer distribution shown in Figure 1 as gained from molecular modelling, along with the cycloaddition preferences of the parent o-benzoquinone and the 3,6-di-tert-butyl substituted o-benzoquinone, are presented in the subsequent paper. [8]

Cycloaddition of o-benzoquinone. Catechol 23 was oxidised by iodobenzene diacetate to produce o-benzoquinone 24 in situ [9] and this was trapped by norbornadiene 9 to form the molrac dione 25 as a stable orange solid in 60% yield, along with products 26-28 as observed minor components. Dione 25 is stable at room temperature and can be further reacted with dimethylacetylene dicarboxylate (DMAD) in the presence of ruthenium catalyst (RuH2CO(P(Ph)3)3) [10] to form adduct 29 (Figure 2).

The formation of 25 as a major product occurs via a [4 + 2]p Diels-Alder cycloaddition. Similar to the o-chloranil reaction, attack can be either endo- or exo- to the norbornadiene ring and so there are four stereochemical dione products as well as two hetero-Diels Alder ether products possible. An examination of transition structure energetics has been employed in these Diels-Alder reactions in an attempt to understand product distributions. These results are presented in the subsequent paper [8]. The theoretical analysis reveals that dione 25 should be the dominant product, as observed by experiment.

The mixture of diones 25-28 was transformed to quinoxalines 30-33 as described above for the o-chloranil compounds 18-21. The product stereochemistry was establised on the basis of the characteristic ¹H-NMR chemical shifts. The chemical shifts of methylene protons Ha and Hb in adduct 30 occurs at d=1.18 and 2.76 while in adduct 31 these proton are shielded by the aromatic ring and appear at d= -0.54 and 0.86, respectively. Furthermore, endo- protons Hc in the linear product 30 are more shielded (d=2.09), as compared to the product 31 (d=1.77). Endo- product 32 methylene proton signals Ha and Hb are found at d=1.43 and 1.77, respectively, while the exo protons are found to be at d=2.60. Also the ! norb ornene olefinic protons are shifted to 6.7 ppm due to effects of the second double bond held in close proximity.

t-Butylbenzoquinone cycloadditions. In an effort to obtain an alternative dione to o-chloranil to react with norbornadiene, the tert-butyl substituted benzoquinone (38) (Figure 3) was targeted for synthesis since similar molecules have been observed to undergo cycloaddition reactions.[11,12] This material should enhance the solubility of any cycloaddition products as well as leaving an olefin available for derivatisation in adducts such as 40.

The synthesis of 38 was accomplished following the literature procedure of Paquette et al. [12] as outlined in Figure 3. Tri-t-butylphenol was treated with bromine in MeOH/AcOH to yield 35 in quantitative yield, and this was further reacted with sodium acetate to give 36 in 88% yield. Irradiation of a benzene solution of 36 with a medium pressure 540W mercury lamp for 2 hours resulted in a photochemical rearrangement to yield 37 as a fluffy white solid. Oxidation of 37 with manganese chloride and oxygen produced the benzoquinone as a dark solid.

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Quinoxaline 18.

¹H NMR (CDCl3): d 1.47 (1H, d of t, Jd=10.3 Hz, Jt=0.9 Hz); 2.02 (1H, d, J=10.3 Hz); 2.42 (2H, d, J=0.9 Hz); 3.29 (2H, t, J=1.8 Hz); 6.33 (2H, t, J=1.8 Hz); 7.80 (2H, m); 8.18 (2H, m); m.p. 190 ^oC.

Quinoxaline 19.

¹H NMR (CDCl3): d -0.67 (1H, d, J=10.5 Hz); 0.85 (1H, dt, Jd=10.5 Hz, Jt=1.5 Hz); 2.87 (2H, d, J=1.3 Hz); 2.93 (2H, d, J=1.6 Hz); 6.1 (2H, m), 7.80 (2H, m); 8.18 (2H, m).

Quinoxaline 20.

¹H NMR (CDCl3): d 1.54 (1H, d, J=8.8 Hz); 1.73 (1H, dt, Jd=8.8 Hz, Jt=1.7 Hz); 3.05 (2H, t, J=1.7 Hz); 3.26 (2H, d, t, J=1.7 Hz); 6.21 (2H, t, J=1.7 Hz); 7.80 (2H, m); 8.19 (2H, m).

�Bird cage� compound 22. The �bird cage" precursor 20 (37 mg, 0.09 mmol) was dissolved in CDCl3 (400 ml) and irradiated at 300 nm for 50 minutes (Pyrex NMR tube). 1H NMR revealed the loss of olefinic resonances and the emergence of a methine signal. Solution was taken to dryness and material purified by column chromatography (silica) eluting with DCM / petroleum spirit (1:1) to give 22 as a pale solid, (m.p. 300 ^oC). Accurate mass: Found: 409.9727, calculated: 409.9727.

¹H NMR (CDCl3): d 1.74 (1H, dt, Jd=12 Hz, Jt=1.8 Hz); 2.00 (1H, d, J=12 Hz); 2.92 (2H, d, J=1.8 Hz); 3.23 (2H, t, J=1.8 Hz); 3.50 (2H, q, J=1.8 Hz); 7.84 (2H, m); 8.29 (2H, m);

¹³C: 36.7, 46.8, 50.9, 55.8, 77.4, 80.5, 129.5, 130.6, 142.2, 146.3.

Tetracyclo[6.2.2.1^3,60^2,7]trideca-4,11-diene-9,10-dione 25. Catechol 23 (1.1 g, 10 mmol) along with 9 (160 ml) were dissolved in CH3CN (720 ml) and PiDA (3.8 g, 12 mmol) added portionwise over 5 minutes. The solution was stirred under a N2 atmosphere in the dark for 3 days. Whilst stirring continued, batchwise additions of 23 (1.1 g, 10 mmol) and PiDA (3.8 g, 12 mmol) were added every 2 days for 6 days to facilitate the production of larger amounts of 25. The solvent was removed by rotary evaporation and the resulting solid was triturated with petroleum spirit. Combination and concentration of organic extracts produced a dark yellow solid that was purified by column chromatography (silica) eluting with CHCl3. Recrystallised product from EtOAc/petroleum ether. (Yield 4.38 g, 55 %, m.p. 145 o C).

¹H NMR (CDCl3): d 1.19 (1H, d, J = 9.1 Hz); 2.15 (2H, s); 2.57 (1H, d, J = 9.1 Hz); 2.97 (2H, t, J = 1.7 Hz); 3.53 (2H, t, J = 3.0 Hz); 6.30 (2H, t, J = 1.72Hz); 6.37 (2H, t, J = 3.0 Hz);

¹³C NMR (CDCl3): d 40.6; 43.2; 47.9; 51.9; 131.3; 140.7; 189.2.

Quinoxalines 30-33. Dione mixture (383 mg, 1.91 mmol) in ethanol/CH3CN (1:1, 20 ml) along with phenylenediamine (280 mg, 2.1 mmol) was heated for 2 hours followed by stirring overnight at ambient temperature. Solution was taken to dryness under reduced pressure and purified by column chromatography (silica, eluting with CHCl3/petroleum ether 40%) followed by petroleum ether/ethyl acetate (20%) to give product.

Quinoxaline 30.

¹H NMR (CDCl3): d 1.18 (1H, d, J=8.9 Hz); 2.09 (2H, s); 2.76 (1H, d, J=8.9 Hz); 2.84 (2H, s); 4.09 (2H, t, J=3.6 Hz); 6.19 (2H, s); 7.60-7.66 (2H, m); 7.90 - 7.96 (2H, m);

¹³C NMR (CD2Cl2): d 42.8; 46.7; 46.9; 47.3; 129.1; 129.3; 130.1; 135.4; 140.7; 141.5.

Quinoxaline 31. (estimated from crude spectrum)

1H NMR (CDCl3): d -0.54 (1H, d); 0.86 (1H, d); 1.77 (2H, s); 2.69 (2H, s); 4.0 (2H, m); 5.7 (2H); 6.0 (2H, t, J=3.6 Hz); 7.62-7.65 (2H, m); 7.92-7.96 (2H, m).

Quinoxaline 32. (estimated from crude spectrum)

¹H NMR (CDCl3): d 1.43 (1H, d); 1.77 (1H, d); 2.60 (2H, s); 2.93 (2H, s); 6.0 (2H, s); 6.7 (2H, m).

Dimethyl-pentacyclo[8.2.2.1^3,80^2,90^4,7]pentadeca-5,13-diene-11,12-dione-5,6-dicarboxylate 29. Dione 25 (1.0 g, 5 mmol), DMAD (20 ml) and RuH2CO(PPh3)3 catalyst (246 mg, 0.27 mmol) were dissolved in C6H6 (40 ml) and heated under reflux under a N2 atmosphere for 2 days. The solution was concentrated to dryness and purified by column chromatography (silica) eluting with CHCl3. The product was recrystallised from EtOAc/petroleum ether and pumped under vacuum. (Yield 345 mg, 20%, m.p. 176 ^oC).

¹H NMR (CDCl3): d 0.88 (1H, t, J = 7.2 Hz); 1.11 (1H, d, J = 12.1 Hz); 1.26 (2H, t, J = 7.2 Hz); 1.55 (2H, s); 2.06 (2H, m); 2.15 (1H, d, J = 12.1 Hz); 2.65 (2H, m); 3.78 (6H, m); 6.39 (2H, m).

¹³C NMR (CDCl3): d 27.8; 39.9; 40.9; 42.5; 47.9; 51.9; 53.4; 128.6; 130.8; 132.8; 141.1; 161.1; 187.1.

4-Bromo-2,4,6-tri-tert-butylcyclohexa-2,5-dien-1-one 35. Method by Paquette et al. [12] Tribromophenol (34) (50 g, 0.2 mol) was dissolved in MeOH (250 ml) and glacial acetic acid (250 ml) and cooled in an ice bath. Bromine (12 ml, 0.23 mol) was added dropwise with stirring. Upon completion of addition, H2O (500 ml) was added and the precipitated material removed by filtration. The solids were dissolved in petroleum spirit, washed Na2S2O5 solution (10%, 400 ml), NaHCO3 solution and dried (Na2SO4). Solvent removal yielded 35 as a yellow solid (63.61 g. 98%, m.p. 77 ^oC, lit. 80 ^oC).

¹H NMR (CDCl3): d 1.13 (9H, s); 1.24 (18H, s); 6.90 (2H, s);

¹³C: 25.8, 26.4, 28.8, 29.4, 29.7, 34.9, 39.9, 72.5, 139.8,141.4, 145.2, 184.8.

4-Acetoxy-2,4,6-tri-tert-butylcyclohexa-2,5-dien-1-one 36. Method by Paquette et al. [12] Bromomaterial 35 (10.24 g, 29 mmol) was dissolved in acetic acid (100 ml) along with NaOAc (17.3 g, 21 mmol) and the solution heated at 65 uC for around 20 hours. Water was added and the solution extracted with Et2O (2 x 200 ml). Combined organic extracts were washed H2O, NaHCO3 solution (3 x 300 ml), H2O and dried (Na2SO4). Solvent removal produced a yellow oil that solidified upon standing (8.5 g, 88%) which was used in the next step without further purification.

¹H NMR (CDCl3): d 0.97 (9H, s), 1.23 (18H, s); 2.07 (3H, s); 6.47 (2H, s).

1-Acetoxy-2-hydroxy-3,6-di-tert-butylbenzene 37. Method by Paquette et al. [12] Acetate (36) (2 g, 6 mmol) was dissolved in benzene (1 l) and irradiated with 450W medium pressure mercury lamp through pyrex for 2 hours while N2 was bubbled through the solution. The solvent was removed by rotary evaporation to give a yellow oil which was crystallised from diethyl ether/petroleum spirit to give 37 as a fluffy white solid (0.51 g, 31%, m.p 177 ^oC, lit. 176 ^oC).

¹H NMR (CDCl3): d 1.34 (9H, s); 1.41 (9H, s); 2.41 (3H, s); 4.92 (bs, 1H); 6.75 (1H, d, J=9 Hz); 7.10 (1H, d, J=9 Hz).

3,6-Di-tert-butyl-o-benzoquinone 38. Method by Paquette et al. [12] NaHCO3 (150 mg, 1.8 mmol) was added to a solution of MeOH (16 ml) and water (2 ml) along with MnCl2 (5 mg). Acetate (37) (400 mg, 1.5 mmol) was added all at once and O2 bubbled through the stirred solution for 50 minutes. MeOH was removed by rotary evaporation and the remaining solution extracted with CCl4 (3 x 20 ml) with combined extracts dried (Na2SO4) and concentrated to give a dark green solid. (m.p 186 ^oC, lit. 200-204 ^oC). Material was used without further purification.

¹H NMR (CDCl3): d 1.23 (18H, s); 6.67 (2H, s).

Hetero Diels-Alder adduct 39. t-Butyl benzoquinone 38 (250 mg, 1.1 mmol) was dissolved in benzene (20 ml) along with NBD (500 ml) and the solution was heated in a sealed tube at 80 &127;^oC for 1 day, 100 &127;^oC for 4 days, and 110 &127;^oC for 1 day until the reaction was judged to be complete (NMR). The solution was taken to dryness to give a yellow powder which was adsorbed onto silica and placed atop a column and eluted with petroleum spirit to give 39 (295 mg, 83%, m.p 169 ^oC). Uninterpretable mass spectrum.

¹H NMR (CDCl3): d 1.39 (18H, s); 1.86 (1H, dt, J=2, 9.0 Hz); 2.62 (1H, d, J=9.0 Hz); 3.13 (2H, t, J=2.0 Hz); 3.97 (2H, 2, J=2.0 Hz); 6.17 (2H, t, J=3.0 Hz); 6.84 (2H, s);

¹³C (CDCl3): d 29.9, 34.2, 43.9, 47.4,79.2, 118.6, 136.6, 137.5, 147.9.

Acknowledgements. We are grateful to the Australian Research Council (ARC) for funding.

References.

1. Warrener, M. R.; Johnston, M. R.; Schultz, A. C.; Golic, M.; Houghton, M.; Gunter, M. J. Synlett 1998, 590.

2. Nunn, E. E.; Wilson, W. S.; Warrener, R. N. Tetrahedron Lett. 1972, 2, 175.

3. Warrener, R. N.; Butler, D. N., Russell, R. A. Synlett, 1998, 366.

4. Warrener, R. N.; Johnston, M. R.; Gunter, M. J. Synlett 1998, 593; Johnston, M. R.; Gunter, M. J.; Warrener, R. N. J. Chem. Soc. Chem. Commun. 1998, 2739; Warrener, R. N.; Schultz, A. C.; Johnston, M. R. J. Org. Chem. 1999, 64, 4218.

5. Gunter, M. J.; Warrener, R. N. Chem. in Aust. 1997, 25.

6. Golic, M. Ph. D. thesis, CQU, 1999.

7. Schultz, A. C. Ph. D. Thesis, CQU, 1998.

8. Margetic, D.; Johnston, M. R.; Latter, M. J.; Warrener, R. N. ECSOC-4 subsequent paper, Part II.

9. Muller, G. H.; Waldman, H. Tetrahedron Lett. 1994, 35, 6745.

10. Mitsudo T.; Kokyro, K.; Shingsui, T.; Nakagawa, Y.; Watanabe, Y.; Takegami, Y. J. Org. Chem. 1979, 25, 4492.

11. Liao, C.-C.; Hsieh, H. P.; Lin, S.-Y. J. Chem. Soc., Chem. Commun. 1990, 545; Nair, V.; Kumar, S. Synlett 1996, 1143.

12. Paquette, L. A.; Hefferon, G. J.; Samodral, R.; Hanzawa, Y. J. Org. Chem. 1983, 48, 1262.

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